Method and apparatus for pH recording

ABSTRACT

For continuous or intermittent monitoring or recording of the in vivo plasma pH of a patient, the patient&#39;s acid base status is established with performance of at least one in vitro determination on a blood sample from the patient, and for a period of some hours thereafter, the patient&#39;s in vivo plasma pH is determined on the basis of this initial acid base status and the results of non-invasive measurements of the patient&#39;s actual blood Pco 2 .

This is a continuation of application Ser. No. 12,847, filed Feb. 16,1979, now abandoned.

The present invention concerns a method and an apparatus for continuousor intermittent monitoring of pH in a patient's blood or plasma, belowcalled the patient's "in vivo plasma pH".

In various clinical situations, it is important to have continuousinformation about the patient's in vivo plasma pH over a period. Thus,it is known that children seldom survive a decrease in in vivo plasma pHto below 6.8, and that on the whole a decrease in pH has manysignificant effects, including stimulation of the periferic and centralchemoreceptors, increase in the plasma concentration of potassium,increase in the plasma phosphate concentration and decrease in theintracellular concentration of organic phosphates, a considerableincrease of the plasma concentration of adrenaline and nor-adrenaline,and an increase of the blood pressure. Vasodilatation in the brain,which is probably due to a decrease in the pH of the extracellular brainliquor, causes an increased blood flow in the brain and an increasedintracranial pressure with headache and, at last, coma as symptoms. Thetherapy in the case of dangerously low pH values is, for example,artificial ventilation. In recent years, also infusion of sodiumbicarbonate has been used for correcting a dangerously low pH innew-borns. A too high plasma pH may also result in a dangerous conditionand may, for example, increase the protein binding of Ca.sup. ++resulting in a decrease of free ionized calcium which may lead to musclefibrillations and even tetanus.

In the known art, a monitoring of a patient's in vivo plasma pH may beobtained either by withdrawing blood samples from the patient at thetimes desired, or by using a transcutaneous pH electrode of the kinddescribed for example in U.S. Pat. No. 4,033,330, or a measuring chamberfor determining electromagnetic radiation of the kind disclosed in U.S.Pat. No. 4,041,932. The former method permits only the obtainment of"instantaneous pictures" at the time of the blood sample withdrawal, andanother disadvantage is that the patient is, each time, subject to theinconveniences caused by the withdrawal of blood samples. The devicesdisclosed in the above-mentioned U.S. patent speifications requireremoval of the surface layer of the skin where they are to be applied,which, again, leads to considerable inconveniences to the patient.

The present invention provides a method which permits continuous, or, ifdesired, intermittent monitoring of a patient's in vivo plasma pH over aperiod, without the necessity of using electrodes which require removalof skin layers, and without the necessity of repeated withdrawals ofblood samples.

The method of the invention for continuous or intermittent monitoring ofa patient's in vivo plasma pH comprises establishing the patient's acidbase status (in the following called the initial acid base status) withperformance of at least one in vitro determination on a blood samplewithdrawn from the patient, and thereafter determining the patient's invivo plasma pH on the basis of the thus established initial acid basestatus and on the basis of continuously or intermittently registeredresults of a non-invasive measurement of the patient's actual bloodPco₂.

The method of the invention permits the continuous or intermittentmonitoring of a patient's in vivo plasma pH with sufficient exactitudeover a period, in practice a period of several hours, without thenecessity of performing determinations on more than one blood samplefrom the patient. In the process of the invention, one utilizes at leastone in vitro determination on the blood sample withdrawn from thepatient for establishing the patient's initial acid base status. Theremaining pH determinations in the period thereafter are performed onthe basis of the results of the non-invasive measurement of thepatient's actual blood Pco₂, as the invention, such as described ingreater detail below, utilizes the fact that once the patient's acidbase status has been established, the pH may, for a considerable periodthereafter, be expressed on the basis of the blood Pco₂.

The very measurement of the patient's blood Pco₂ in a non-invasivemanner does not constitute any part of the present invention. Apparatusfor non-invasive, especially transcutaneous, determination of bloodPco₂, in other words, the partial pressure of CO₂ in the blood, hasrecently been developed and is currently being developed. Suitablesensors for relatively inconvenience-free transcutaneous Pco₂determinations are Pco₂ electrodes which are heated to above skintemperature and which, when applied against the skin, heat the skin inthe measuring area, vide for example Anesthesiology, Vol. 21, No. 6,November-December 1960, pages 717-726, especially 722, and Anaesthesist,22, 379-380 (1975), Journal of Applied Physiology, 41, No. 3, September1976, 442-447, and The Lancet, May 7, 1977, 982-983. However, also othernon-invasive methods permitting the determination of a patient's bloodPco₂ are known, vide for example U.S. Pat. No. 4,005,700 which disclosesthe use of mass spectrometry on gas in equilibrium with heated skin.

Several workers have investigated the acid base conditions of blood,especially human blood, and comprehensive collections of parameter setshave been prepared, for example in the form of tables, algorithms,computer programs, nomograms and curve nomograms. By means of these onecan, from a given set of parameters for a blood sample, for example pH,Pco₂ and hemoglobin concentration, determine other parameter values,including for example the bicarbonate concentration in plasma, actualbase excess of the blood and, when the oxygen saturation (defined below)is known, also base excess of completely oxygenated blood, the blood'sbuffer base and standard bicarbonate.

A detailed review of the acid base status of the blood is given by OleSiggaard-Andersen in "The Acid-Base Status of the Blood", 4th edition,Munksgaard, Copenhagen, 1974, issued simultaneously in the United Statesby William & Wilkins Company, Baltimore. In this book, the author statesvarious suitable parameter relations as equations, nomograms and curvenomograms, but also mentions other parameter relations stated by otherworkers.

Of special interest in this connection is the so-called acid base statuswhich in principle is determined when at least two acid base quantitiesfor the patient's extracellular liquid are determined, typically the pHand Pco₂ of the arterial blood. In this connection the expression "thepatient's acid base status" indicates a set of connected values for pHand Pco₂ in the patient's arterial blood or, with sufficientapproximation, arterialized capillary blood, for example from the earlobe. In accordance with this, the patient's acid base status may bedetermined by measuring of pH and Pco₂ on an arterial blood sample orcapillary blood sample from the patient, when the said blood sample hasbeen withdrawn and transferred to the measuring apparatus underanaerobic conditions.

It has been empirically ascertained and theoretically supported that apatient's acid base status, expressed as connected values of pH andPco₂, will always change according to a certain relation, as long as thepatient has not had any substantial chemical exchange with thesurroundings other than by respiration, except in the rare (and easilyascertainable) cases where the patient undergoes abnormal metabolicdisturbances as for instance in case of diabetes. This is, explained ina simplified manner, due to the fact that changes in Pco₂ (as byrespiration) changes pH without influencing the concentration ofnon-carbonic acid or base. In other words, for a given concentration ofnon-carbonic acid or base, a certain pH will correspond to a given Pco₂.Considerable changes in the relation between Pco₂ and pH will arise whenthe patient has chemical exchange with the surroundings in other waysthan by respiration, for example by blood transfusion. When, however,such considerable changes do not occur, the relation between Pco₂ and pHwill be established over a period of several hours, in practice up to3-10 hours, and this fact is utilized in the present invention. Minorvariations in the relation between Pco₂ and pH may arise due to changesin the oxygen saturation (defined below). In practice, these variationsdue to the changes in the oxygen saturation are so small that they canbe ignored in most cases. But the method of the invention also permitstaking them into consideration.

On the basis of the above-mentioned explanation it is understood thatwhen a patient's acid base status has been established, an unambiguousrelation between pH and Pco₂ for a considerable period will exist inpractice. By using the parameter relation between Pco₂ and pH, theregistered results of the Pco₂ measurement may be expressed as pHvalues.

The relation between blood parameters are not unanimously indicated byall workers, and a quite "absolute" parameter relation which isincontrovertibly true for all patients, can hardly be given. The variousproposed parameter relations are therefore to be considered asapproximations which have shown their applicability and sufficientexactitude in practice. Values fixed by definition form part of theparameter relations and their calculations for certain parameters incertain relations, and these values may also vary from worker to worker.In principle, any parameter relation which has been found to beclinically applicable may be used for the purpose of the presentinvention for transformation of the transcutaneously measured Pco₂ topH, whether this parameter relation is expressed as equations,nomograms, curve nomograms or computer programs. In connection with thefollowing explanation of the invention, however, reference is made tothe parameter relations which are stated by Ole Siggaard-Andersen in theabove work and which enjoy general acceptance.

According to the present invention, the patient's initial acid basestatus is established with performance of at least one in vitrodetermination on a blood sample withdrawn from the patient. As mentionedabove, a determination of pH and Pco₂ in an anaerobically withdrawnarterial or capillary blood sample from the patient will establish thepatient's acid base status.

The determination of pH and Pco₂ on an anaerobically transferredarterial or capillary blood sample withdrawn from the patient isperformed by means of a pH transducer and a Pco₂ transducer,respectively. They may be electrodes of a type known per se, which arecalibrated in advance so that they, when measuring, indicate true valuesfor pH and Pco₂. For establishing the patient's initial acid base statusit is sufficient to perform one of these in vitro determinations on aanaerobically transfered arterial blood sample withdrawn from thepatient, in practice a determination of pH. The other value, in practicePco₂, may, instead of being determined on the blood sample, be the valueregistered from a non-invasive measurement performed on the patient witha calibrated transducer simultaneously with the withdrawal of the bloodsample.

According to an aspect of the present invention, a Pco₂ measurement isperformed in vitro on the anaerobically transferred arterial orcapillary blood sample, even when an in vivo, that is, non-invasive,measurement of Pco₂ has been performed simultaneously with thewithdrawal of the blood sample. For the in vitro Pco₂ measurement, acalibrated Pco₂ transducer, for example a calibrated Pco₂ measuringelectrode, is used. Thus the difference between the in vitro measuredand the in vivo measured Pco₂ may be used directly for calibration ofthe in vivo Pco₂ measuring device in the condition in which it ispositioned for the purpose of the measurement, the reading orregistration of the in vivo Pco₂ measuring instrument being corrected onthe basis of the difference.

However, the method of the invention does not even necessitatemeasurements on an anaerobically transferred arterial or capillary bloodsample from the patient. The initial acid-base-status may also beestablished on the basis of a non-anaerobically transferred bloodsample, whether it is an arterial, a capillary or a vein blood sample.In this case, however, it is necessary to perform measurement ofsufficient blood parameters for determining the pH, Pco₂ and hemoglobincontent of the sample (in practice this usually means determination ofthe pH and Pco₂ of the sample and of a further blood parameter which iseither the hemoglobin content or another blood parameter being afunction of the hemoglobin content (or the hemoglobin content may as anapproximation be fixed as 9.3 mmol/liter) and for the establishing, alsothe result of a measurement of the patient's actual blood pH and Pco₂performed simultaneously with the withdrawal of the blood sample isrequired, which in practice may be a non-invasive Pco₂ measurement witha calibrated Pco₂ measurement unit. With this set of parameters andusing known parameter relations for the in vitro acid base status of theblood, for example such as stated by Ole Siggaard-Andersen in theabove-mentioned work, it is possible to determine the patient's acidbase status at the moment of the withdrawal of the blood sample.

This establishing of the patient's initial acid base status may inprinciple be performed by determining, on the basis of the hemoglobindetermination (or the hemoglobin fixed, as an approximation, at 9.3mmol/liter) and the connected values of pH and Pco₂ measured on theblood sample, the function along which connected values of pH and Pco₂vary for the blood sample in question, and subsequently inserting thePco₂ measured at the moment of the withdrawal of the blood sample anddetermining the corresponding pH. The calculations in question may beperformed by using the above-mentioned parameter relations in the formof equations, computer programs, nomograms or curve nomograms. Thisestablishing of the patient's acid base status will be sufficientlyexact in most cases.

A further increase of the exactitude when determining the patient'sinitial acid base status on the basis of a non-anaerobically withdrawnblood sample is obtained by correcting for possible differences betweenthe oxygen saturation in the blood sample at the time of the in vitrodetermination and the oxygen saturation at the time of withdrawal of thesample.

The oxygen saturation is defined as the ratio between hemoglobinsaturated with oxygen and the sum of hemoglobin saturated with oxygenplus hemoglobin without oxygen and may, for example, be determinedphotometrically by means of a so-called oxymeter or may be calculated onthe basis of a determination of Po₂. When it is desired to correct forpossible differences in oxygen saturation between the patient's blood atthe time of the withdrawal of the sample and the blood sample in thecondition in which it is subjected to measurement in vitro, it isnecessary to use the result of a Po₂ measurement or a saturationmeasurement, preferably performed on the patient in a non-invasive way,at the time of the withdrawal of the blood sample, together with theresult of a corresponding determination of the oxygen saturation, thatis, either by a Po₂ measurement or by means of photometric measuringapparatus, performed simultaneously with the pH and Pco₂ determinationon the blood sample. In principle, the correction of the patient's acidbase status to compensate for differences between the oxygen saturationof a non-anaerobically transferred blood sample and the oxygensaturation at the transfer moment may be performed by displacing, on thebasis of the difference in the oxygen saturation, the curve forconnected values of pH and Pco₂, inserting, on the displaced curve, thePco₂ measured at the sample withdrawal moment, and reading thecorresponding pH. As mentioned, the correction for the saturation willin practice be relatively small as it appears from the examples.

Irrespective of how the patient's initial acid base status isestablished, it may be desirable, for the sake of accuracy, continuouslyto take into consideration possible changes in the oxygen saturation.This, of course, necessitates that the initial oxygen saturation beestablished which, for the anaerobically transferred arterial orcapillary blood sample, is done simply by a photometric measurement or aPo₂ measurement on the blood sample.

When the patient's initial acid base status has been established in oneof the above-described ways, the further monitoring of the pH accordingto the invention takes place on the basis of the thus establishedinitial acid base status and on the basis of continuously orintermittently registered results of non-invasive measurement of thepatient's actual blood Pco₂. Also in this connection, accepted parameterrelations are used, the condition being that the function used forconnected values of the patient's extracellular pH and Pco₂, theso-called "in vivo CO₂ equilibration line" or "Base Excess line",includes, at unchanged oxygen saturation, the initial acid base statusas a function value. In principle, this function is, in suitablerepresentations, a straight line. As a point on this line has beenestablished as the patient's initial acid base status in theabove-described way, only the establishing of the slope is necessary forthe further application. This may be done by using empiric/definitionvalues, for example a definition value of 3.7 mmol/liter for thehemoglobin concentration in vivo. The below examples show variousmethods for determining the patient's in vivo base excess line.

In the further monitoring of the patient, the pH is determined each timeon the basis of the continuously or intermittently registered results ofthe non-invasive blood Pco₂ measurement by means of the thus establishedBase Excess line. All the time, instead of the registered Pco₂ inquestion, the corresponding pH is read. The expression "is read" is notto be taken literally; in practice the conversion units will usually,instead of curves and curve sensors, include computers in which theparameter relations in question are programmed in advance. To obtain thehighest exactitude, also changes in the oxygen saturation may bemonitored by means of a non-invasion transducer, for example anon-invasive Po₂ electrode or an ear oxymeter; when the oxygensaturation changes, the Base Excess line is displaced correspondingly.

The present invention also concerns an apparatus for use in the methodof the invention. This apparatus comprises an input for signalsrepresenting the result of a non-invasive Pco₂ measurement and an inputfor introducing at least one blood parameter determined by in vitromeasuring on a blood sample, and further comprises a pH registrationunit which is connected to the first mentioned input through aconversion unit, the conversion unit being adapted to perform theconversion of the received Pco₂ signals into pH units as a function of aparameter set introduced into the conversion unit, the parameter setrepresenting an initial acid base status and comprising at least oneblood parameter determined by in vitro measurement and introducedthrough the last-mentioned input.

The transmission unit of such an apparatus will in practice preferablycomprise a microcomputer which has a sufficient memory for the purpose,and into which the parameter relations, expressed as for instanceequations (vide, e.g., the examples), have been introduced, themicrocomputer establishing, at given inserted parameter set representingan initial acid base status, the slope of the Base Excess line throughthe point corresponding to this acid base status, and thereafterconverting measured Pco₂ values and expressing them as pH. In thespecial case where the oxygen saturation or oxygen saturationdifferences are ignored in these conversions, the conversion unit andits programming may be particularly simple, as, in this case, all BaseExcess lines converge, with sufficient approximation, to a single point(vide Example 4.d).

In accordance with what has been explained above, the parameter setwhich represents an initial acid base status may be established indifferent ways, but each time the parameter set comprises at least oneblood parameter which is either the pH determined on a blood samplewithdrawn from the patient or a blood parameter of which is a functionof this pH as described above, the parameter set which represents aninitial acid base status may completely be determined in vitro on ananaerobely withdrawn blood sample, and the whole parameter set whichrepresents this acid base status will thus be introduced into theconversion unit through the input adapted thereto. As it appears fromthe above disclosed, it is also possible to establish the parameter setrepresenting the initial acid base status, by using both one or more invitro measured blood parameters and a non-invasive measurement ofusually Pco₂ (and possibly Po₂ or the oxygen saturation) performedsimultaneously with the blood sample withdrawal in question. In thiscase, the establishing of the initial acid base status is performed bythe conversion unit on the basis of partly the "in vitro input" andpartly the "in vivo input".

An apparatus according to the present invention is suitably equippedwith a unit, in connection with the in vitro input, for introduction ofthe blood parameter(s) determined in vitro for establishing the initialacid base status. This unit may, for example, be a pH measuringequipment of the conventional kind (for introduction of in vitro pH), ablood gas equipment (from which in vitro pH and, according to theconstruction and design of the blood gas equipment, other in vitro bloodparameters which might be necessary for establishing the initial acidbase status in question, may be introduced including, for example, invitro Pco₂, in vitro hemoglobin content and in vitro Po₂). The unit mayalso simply be a keyboard, which in addition to pH may be adapted tointroduce any desired in vitro blood parameter or blood parameter set,including a complete initial acid base status determined with separateequipment. The apparatus may also be equipped with both a measuringunit, for example a pH measuring equipment or a blood gas equipment, anda keyboard, the keyboard then being useful for introducing parameterswhich cannot be measured on the measuring unit or which in the specificsituation will not be measured on the measuring unit.

In a special embodiment the apparatus comprises, besides the pHregistration unit, a Pco₂ registration unit which is in connection withthe input of signals representing the result of a non-invasive Pco₂measurement, so that the invasively measured Pco₂ values may be read onthe apparatus. For use in the cases where it is desired to take theoxygen saturation into consideration, it is suitable that the apparatuscomprises an input for signals representing the result of a non-invasivePo₂ measurement or oxygen saturation measurement, and that this inputcommunicates with the conversion unit. This permits the result of thenon-invasive Po₂ measurement or oxygen saturation measurement to beincluded in the calculation performed by the conversion unit, such asdescribed above. When the apparatus comprises an input for signals froman in vivo Po₂ measurement, it may be desirable also to include a Po₂registration unit in the apparatus, connected with the said input, sothat one can read information about the measured Po₂ value on theapparatus, or have the apparatus deliver this as read-out.

According to a preferred embodiment of the apparatus, it comprises asynchronizing unit which, when activated, stores, in the conversionunit, the non-invasive Pco₂ value measured at the activating timeand--if the apparatus also comprises an input for a non-invasive Po₂electrode or an ear okimeter, and it is desired, for the measurement inquestion, to take into consideration the oxygen saturation--also thenon-invasively measured Po₂ value or oxygen saturation value registeredat the activating time. When this synchronizing unit is activated at thetime where a blood sample is withdrawn from the patient, it is securedthat the non-invasively measured initial Pco₂ and optional Po₂ orsaturation value stored in the conversion unit is/are the value(s) whichexactly applied at the time of the withdrawal of the blood sample, andhence is/are the value(s) to be related to the in vitro measurement.This is relevant for all the cases where the in vitro measurement is tobe combined with an in vivo measurement performed simultaneously withthe blood sample withdrawal, in other words for example when the invitro measurement is performed on a non-anaerobically transferred bloodsample, or where the in vitro measurement on an anaerobicallytransferred blood sample does not comprise the complete parameter setrepresenting acid base status. Another case in which a synchronizationbetween the blood sample withdrawal and a non-invasive measurement isdesired is when it is desired to take the oxygen saturation intoconsideration, and the initial oxygen saturation is determined on thebasis of a non-invasive Po₂ measurement or oxygen saturationmeasurement. A further utilization of synchronization between the bloodsample withdrawal and a non-invasive measurement is for calibration ofthe non-invasive transducer. For example, the pH measuring instrumentsignal from an initial measurement on an anaerobically transferredarterial or capillary blood sample together with the simultaneous signalfrom the non-invasive Pco₂ transducer may simply serve for automaticcalibration, by the conversion unit, of the read-out of the non-invasivePco₂ transducer, expressed as pH. (Another calibration possibility ofthis kind is that an initially determined pH pertaining to the acid basestatus of the patient is, by means of the keyboard, read into ortransferred into the pH registration equipment of the apparatus). Thesynchronization unit in its simplest embodiment may be a buttonpositioned on the apparatus and operated manually at the time of theblood sample withdrawal, or it may comprise an input which through anelectric cord or cable is in communication with a button positioned atthe blood sample withdrawal station for manual operation, or with atransducer connected to the blood sample withdrawal apparatus, saidtransducer being automatically activated when the blood samplewithdrawal is performed.

The invention is now described in greater detail with reference to thedrawing, in which

FIGS. 1-6 show curve nomograms illustrating the determinations performedin the below examples, and

FIG. 7 is a schematic representation of an apparatus according to theinvention.

FIGS. 1-6 are discussed in greater detail in connection with theexamples.

Reference is made to FIG. 7 which is a schematic representation of anembodiment of an apparatus of the invention. A module 10 comprises aninput part 11 which, in the embodiment shown, is equipped with a Pco₂registration unit being for example a digital display 15 which, throughan amplifier (not shown) communicates with an input 13a for signals froma non-invasive Pco₂ transducer 13 (shown as a heated Pco₂ electrode),and which shows the non-invasively measured Pco₂ value designated "T_(c)-Pco₂ ". The input part 11 may additionally comprise for example a Po₂registration unit in the form of for example a digital display 16, whichin a corresponding way, through an amplifier, communicates with an input14a for signals from a non-invasive Po₂ transducer 14 (shown as a heatedPo₂ electrode) and which shows the non-invasively measured Po₂ value,designated "T_(c) -Po₂ ". In the embodiment shown, the module 10 furthercomprises a pH registration unit 12 with for example a digital display17 showing the calculated in vivo pH value, designated "in vivo pH". Asan alternative or supplement to the digital displays 15, 16 and 17, themodule may comprise a printing unit 18 which through a line 18acommunicates with the respective registration units, or the module maycomprise any other registration unit, for example a central registrationand storing unit 19 of any suitable kind, which may for example serveseveral apparatuses of the kind described and which in the embodimentshown communicates with the registration units through a line 19a. Theinput part 11 supplies, via a connection 20, signals, suitably indigitalized form, representing the non-invasively measured Pco₂ and (ifa non-invasive Po₂ measurement is performed) via a connection 32signals, also suitably in digitalized form, representing thenon-invasively measured Po₂, to an interface part 22 of a conversionunit 21. The interface part 22 is equipped with an input 25a and/or 27afor introducing in vitro measured parameters, the input 25a beingconnected, via a connection 25, with a manually operated keyboard 24,and the input 27a being connected, via a connection 27, with a pH meteror blood gas equipment 26. The interface part is also equipped with asynchronizing unit which may be a manually operated button 28 or asuitable transducer or remote control button 29 which, through aconnection 30, is connected to the interface part. The interface part isconnected to a computer part 23 of the conversion unit 21, which,through a connection 31 is connected to the in vivo pH registration unit12.

In practice, the design of the single modules and the extend to whichthey are built together will be dictated by the particular facilitiesand conditions prevailing at the location of use. One suitable apparatusfor many of the relevant uses will comprise the module 10 built togetherwith the conversion unit 21 and equipped with the keyboard 24. Such anapparatus may, according to what is needed, comprise solely the Pco₂transducer 13 as transcutaneous measuring unit, or it may comprise boththe Pco₂ transducer 13 and the Po₂ transducer 14. Alternatively, theapparatus consisting of the modules 10 and 21 may be built together witha blood gas measuring equipment or a pH measuring equipment 26, or itmay suitably simply be equipped with the input 27a for on line transferof measuring results from a pH measuring equipment or blood gasmeasuring equipment. In another embodiment, the conversion unit 21 maybe built together with an in vivo pH registration unit 12a with, forexample, a digital display 17a and/or a printing unit 18' or anotherregistration unit 19', which through connections 18'a or 19',respectively, is connected with the registration unit, the computer part23 in this case communicating with the pH registration unit through aconnection 31a. This way of building together the units may be practicalfor larger plants in which a central conversion and registration unitcalculating in vivo pH serves a number of individual non-invasive Pco₂registration units, each comprising non-invasive transducer 13 and inputpart 11 with amplifier, etc., which in this case is not itself equippedwith any display. An apparatus consisting of the conversion unit 21 andthe pH registration unit 12a may also be a practical supplement forexisting non-invasive Pco₂ measuring equipment.

The invention is further illustrated in the below examples.

Examples 1 illustrates how a curve nomogram is used, especially inconnection with the establishment of a patient's initial acid basestatus from in vitro measurements performed on a non-anaerobicallytransferred blood sample.

Example 2 shows the same type of determination, but in this caseperformed by calculation.

Example 3 illustrates various determinations of the patient's initialacid base status.

Example 4 illustrates the use of the patient's acid base status forestablishing the in vivo Base Excess line using partly nomogram andpartly calculation, and the use of the in vivo Base Excess line fordetermining the in vivo plasma pH value utilizing results ofnon-invasive determinations of the patient's actual blood Pco₂.

In connection with the examples the following definitions are used:

Actual Base Excess (ABE): The difference in concentration of strong basein the blood between on the one hand the actual blood sample and on theother hand the same blood titrated with a strong base or acid to pH 7.4,Pco₂ 40 mm Hg and a temperature of 37° C. The titration is performed atconstant oxygen saturation which is the same as the one in the arterialblood of the person.

Base Excess (BE): Same definition as ABE, but with the titrationperformed at complete oxygen saturation.

In Vivo Base Excess (SBE): Same as ABE, but with a fixed standardhemoglobin concentration of 3.7 millimol/liter.

Saturation (Sat): Sat=HbO₂ /(HbO₂ +Hb) in which HbO₂ is theconcentration of hemoglobin saturated with oxygen, and Hb is theconcentration of hemoglobin without oxygen.

Buffer Base (BB): Indicates the concentration of buffer anions in theblood when all hemoglobin is present as HbO₂.

Normal Buffer Base (NBB): Is the buffer base value of blood with pH 7.4,Pco₂ 40 mm Hg and temperature 37° C.

    NBB=41.7+0.68×Hb mmol/liter                          (1)

Actual Buffer Base (ABB): Buffer Base value at actual oxygen saturation(is only used as a calculating quantity.

    ABB=BB+0.31×Hb (1-Sat) mmol/liter                    (2)

Besides, the following relations exist between the above-mentionedquantities:

    BE+BB-NBB=BB-(41.7+0.68×Hb) mmol/liter               (3)

    ABE=BE+0.31×Hg (1-Sat) mmol/liter                    (4)

    ABB-ABE=NBB mmol/liter                                     (5)

EXAMPLE 1

By means of a blood gas equipment (Radiometer ABL 2), the followingvalues have been measured on a non-anaerobically transferred bloodsample:

    pH=7.2

Pco₂ =30 mm Hg

    Po.sub.2 =200 mm Hg˜Sat=1

    Hb=10 millimol/liter.

Simultaneously with the withdrawal of the blood sample, the followingvalues were measured transcutaneously on the patient:

    Pco.sub.2 =50 mm Hg

    Po.sub.2 =37.3 mm Hg˜Sat=0.5

On the basis of these parameters, the initial acid base status of thepatient is established with maximum exactitude (that is, taking intoconsideration the oxygen saturation) in the following way:

Firstly, a point (A) is plotted in the curve nomogram in FIG. 1,corresponding to the pH and Pco₂ of the blood sample. Utilizing the Hbvalue, the line I from BE=0 to BB=41.7+0.68×10=48.5 (confer equation(1)) is drawn. This line is thereafter displaced the same number ofunits along the BB and BE curves, until it passes through point (A)(line II). Equation (5) is now fulfilled.

Thereafter, the point (B) is plotted on line II corresponding to thetranscutaneously measured Pco₂. The pH in this point is 7.098. Point Brepresents the patient's initial acid base status, when the saturationdifference between the patient and the non-anaerobically transferredblood sample is not taken into consideration. Correction for thissaturation difference to obtain the more exact value is performed bydisplacing the Base Excess line (II) by the quantity 0.31×10(1-0.5)=1.55 along both the BE and the BB curves (equation (2) and (4)).This results in line III which passes through ABE=-14.1 and ABB=34.4,while line II passed through ABE=BE=-15.7 and ABB=BB=32.8. On line IIIthe transcutaneously measured Pco₂ (50 mm Hg) is not plotted, and pH inthe resulting point (C) is 7.126. Hence, the patient's initial acid basestatus was: Pco₂ 50 mm Hg, pH 7.126.

EXAMPLE 2

From a blood sample withdrawn from a patient and transferred in anon-anaerobical manner, the following values have been measured by meansof a blood gas equipment:

    pH=7.2

    Pco.sub.2 =30 mm Hg

    Po.sub.2 =200 mm Hg˜Sat=1

    Hb=10 millimol/liter.

Simultaneously with the withdrawal of the blood sample, the followingvalues have been measured transcutaneously:

    Pco.sub.2 =50 mm Hg

    Po.sub.2 =37.3 mm Hg˜Sat=0.5.

Now follows an explanation of how the calculation of the patient'sinitial acid base status is performed on this basis. The calculation maybe performed by means of a computer. The explanation is illustrated bythe curve nomogram in FIG. 2. The coordinates of the BE and BB curvesare known (for example from p. 54 in the work by Ole Siggaard-Andersenpreviously mentioned), and ABE may be calculated with goodapproximation.

The point A in FIG. 2 represents the parameter set measured on the bloodsample: pH=7.2 and Pco₂ =30 mm Hg. Calculation is performed:

    ABE=Z(1-0.000383×Hb(Z+25.11)-2.755×Hb)         (6)

wherein

    Z=(1-0.0230×Hb)(HCO.sub.3 -24.5+(8+2.25×Hb)(pH--7.4)) (7)

and HCO₃ is the bicarbonate concentration in plasma which may be foundby: ##EQU1## ABE is calculated to -15.88 millimol/liter (point E).ABB=NBB+ABE=41.7+0.68×Hb+ABE=32.67 millimol/liter (point F).

The co-ordinates of points E and F may be found by linear interpolation:

    pH.sub.E =(pH.sub.-16 -pH.sub.-15)×0.83+pH.sub.-15   (9)

    log Pco.sub.2E =(log Pco.sub.2-16 -Pco.sub.2-15)×0.83+log Pco.sub.2-15                                              (10)

    pH.sub.E =7.253

    Pco.sub.2E =22.58 mm Hg

    pH.sub.F =(pH.sub.33 -pH.sub.32)×0.67+pH.sub.32      (9')

    log Pco.sub.2F =(log Pco.sub.2 33 -log Pco.sub.2 32)×0.67+log Pco.sub.2 32                                              (10')

    pH.sub.F =7.004

    Pco.sub.2F =78.23 mm Hg

From the coordinates for E and F the Base Excess line I may becalculated: ##EQU2##

    log Pco.sub.2 =-2.167×pH+17.072

When the Pco₂ of 50 mm Hg measured simultaneously with the withdrawal ofthe blood sample is inserted, pH 7.094 results (point B).

When the fact that the patient's saturation was 0.5 at the samplewithdrawing time is taken into consideration, the Base Excess line willbe displaced with the quantity 0.31×10(1-0.5)=1.55 along both the BE andthe BB curves (equations 2 and 4) to ABE=-14.28 (G) and ABB=34.25 (H).

The coordinates of points G and H may be calculated according to theequations 9, 10 and 9', 10' with the new values introduced

    pH.sub.G =7.264

    Pco.sub.2G =25.21

    pH.sub.H =7.020

    Pco.sub.2H =81.57

The Base Excess line may thereafter be calculated according to equation11:

    log Pco.sub.2 =-2.090×pH+16.583.

When the trancutaneously measured Pco₂ of 50 mm Hg is inserted, thecorresponding pH is calculated to 7.122 (point C). The patient's initialacid base status was then pH 7.122 and Pco₂ 50 mm Hg.

EXAMPLE 3

(a) Utilizing an apparatus as illustrated in FIG. 7, a patient ismonitored with a transcutaneous Po₂ electrode (14) and a transcutaneousPco₂ electrode (13). A blood sample is withdrawn from the patient (forexample vein blood), and the transcutaneously measured Po₂ and Pco₂values are transferred, by activating the button 28, to the computer(23) the same moment the sample is withdrawn. The values are:

    Po.sub.2 =37.3 mm Hg

    Pco.sub.2 =50.0 mm Hg

The blood sample is kept at room temperature and in contact withatmospheric air. Thereafter, the blood sample is analyzed on blood gasequipment (26), and the same values as are stated in Example 2 aremeasured, in other words corresponding to point A in FIG. 2. Thesevalues are transferred via the connection 27 and the interface part 22to the computer 23. The patient's actual pH is calculated when thevalues in A have been accepted, like in Example 2 as a firstapproximation to 7.094 (point B).

At this pH and the transcutaneously measured Po₂, the saturation iscalculated using the equations: ##EQU3## wherein

    Z=Po.sub.2 ×10(.sup.-0.48(7.4-pH),

    Sat=0.5.                                                   (13)

Thereafter, the in vitro Base Excess line II is calculated for Sat=0.5like in Example 2, and by means of this line and the transcutaneouslymeasured Pco₂ of 50, the patient's actual pH is calculated to 7.122.Hereafter, the patient's initial acid base status is established like inExample 2, and until a change of the transcutaneously measured values isregistered, the three displays will show pH 7.122, Pco₂ 50.0 mm Hg andPo₂ 37.3 mm Hg, respectively. The patient's so-called "in vivo acid basestatus" shows the same values as in Example 2 with the exception of theIII which is fixed per definition to 3.7 millimol/liter in vivo. Thisvalue is of importance for the establishing of the patient's in vivoBase Excess line, confer Example 4.

(b) The patient's in vivo acid base status may also be determineddirectly on a blood sample (arterial blood) withdrawn anaerobically andthereafter analyzed on a separate blood gas equipment:

    pH=7.122

    Pco.sub.2 =50.0 mm Hg

    Po.sub.2 =37.5 mm Hg˜Sat=0.5.

By means of the keyboard 24 the pH and the Pco₂ value and, if the oxygensaturation is to be taken into consideration, the Po₂, are keyed intothe conversion unit 21 via the connection 25.

To the patient's in vivo acid base status also pertain:

Hb=3.7 equivalent Hb in vivo, fixed per definition.

(c) Using an apparatus as illustrated in FIG. 7, a patient is monitoredwith a transcutaneous Po₂ electrode (14) and a transcutaneous Pco₂electrode (13). A blood sample (arterial blood) is withdrawnanaerobically from the patient. Simultaneously with the blood samplewithdrawal, the transcutaneously measured Po₂ and Pco₂ values aretransferred to the computer 23 by activating the button 28.

    Po.sub.2 =37.3 mm Hg

    Pco.sub.2 =50.0 mm Hg

The pH in the blood sample is measured on a separate pH measuringequipment, and the result is keyed in via the keyboard 24.

pH_(actual) =7.122. When this value has been accepted, it is transferredto the computer 23.

The patient's in vivo acid base status is now established:

    pH=7.122

    Pco.sub.2 =50.0 mm Hg

    Po.sub.2 =37.2 mm Hg

    Hb=3.7 millimol/liter, fixed per definition.

(d) Using the apparatus shown in FIG. 7, a patient is monitored with atranscutaneous Po₂ electrode (14) and 1 transcutaneous Pco₂ electrode(13). A blood sample (arterial blood) is withdrawn anaerobically fromthe patient. Simultaneously with the withdrawal of the blood sample, thetranscutaneously measured Po₂ and Pco₂ are transferred to the computer23 by activating the button 28.

    Po.sub.2 =25.0 mm Hg

    Pco.sub.2 =55.0 mm Hg.

The blood sample is analyzed on the blood gas equipment 26. Thefollowing values are found:

    pH=7.122

    Pco.sub.2 =50.0 mm Hg

    Po.sub.2 =37.3 mm Hg,

which by means of the on-line connection 27 is transferred to thecomputer 23.

Using the transcutaneously measured values stored in the computer andthe values measured with the blood gas equipment, the transcutaneouselectrodes are calibrated, transcutaneous Po₂ =f(Po₂ arterial) andtranscutaneous Pco₂ =f(Pco₂ arterial).

The patient's in vivo acid base status is established:

    pH=7.122

    Pco=50.0 mm Hg

    Po.sub.2 =37.3 mm Hg˜Sat=0.5

    Hb=3.7 millimol/liter, fixed per definition.

In all the cases mentioned in Example 3, the in vitro Po₂ and in vivoPo₂ measurements may be replaced with photometric measurements; or theymay be omitted, in which case the in vivo pH is calculated according toExample 4 d).

EXAMPLE 4

(a) Using the curve monogram shown in FIG. 3, the in vivo Base Excessline is established for a patient with the in vivo acid base statusestablished in Example 3.

The construction of the in vivo Base Excess line IV corresponds toExample 1.

    SBE.sub.1 =-12 millimol/liter

    "SBB.sub.1 "=32 millimol/liter.

At a later time, 40 mm Hg is registered as transcutaneously measuredPco₂. While the patient's initial acid base status is represented bypoint C, the pH at the changed acid base status corresponding to thechanged Pco₂ is 7.188 (point D₁). This determination is performed underthe presumption that the saturation is unchanged.

It is found that the patient's saturation has also changed (that is, thetranscutaneously measured Po₂ has changed, for example to 90 mm Hg), thechanged saturation may be calculated from equations 12 and 13, using theph 7.188:

    Sat.sub.2 =0.93.

The Base Excess line V for Sat₂ =0.93 can now be established, using:

    SBE.sub.2 =SBE.sub.1 +0.31×Hb (Sat.sub.1 -Sat.sub.2) (14)

    "SBB.sub.2 "=SBB.sub.2 +0.31×Hb (Sat.sub.1 -Sat.sub.2) (15)

    SBE.sub.2 =-12.5

    "SBB.sub.2 "=31.5.

The Base Excess line corresponding to the changed saturation is shown asV in FIG. 3. The patient's in vivo pH on curve V (in other words atsaturation 0.93) is, at the transcutaneously measured Pco₂ of 40 mm Hg,7.177 (point D₂).

(b) The same establishments as under (a) may be performed bycalculation. The calculation is illustrated in the curve monogram inFIG. 4. The starting point is the same in vivo acid base status as isused under (a).

    pH=7.122

    Pco.sub.2 =50 mm Hg

    Po.sub.2 =37.3 mm Hg˜Sat.sub.1 =0.5

    Hb=3.7 millimol/liter, fixed per definition.

SBE may be calculated from the formulae 6, 7 and 8:

    SBE=-12.23 millimol/liter (point I)

and

    "SBB"=41.7+0.68×lib+SBE=31.99 millimol/liter (point J).

The coordinates of points I and J may be calculated from the equations9, 10, 9', 10':

    pH.sub.I =7.279

    Pco.sub.2 I =28.52 mm Hg

    pH.sub.J =6.998

    Pco.sub.2 J =76.68 mm Hg

From the coordinates for I and J, the in vivo Base Excess line IV may becalculated by means of equation 11:

    log Pco.sub.2 =-1.5286×pH+12.5817.

After some time, the patient's trancutaneously measured Pco₂ has changedto 40 mm Hg, and the corresponding in vivo pH is calculated to 7.183(point D₁).

If a change in in vivo Po₂ to 90 mm Hg is also ascertained, Sat may becalculated from equations 12 and 13, using pH=7.183:

    Sat.sub.2 =0.93.

The Base Excess line V for Sat₂ =0.93 may now be established fromequations 14 and 15:

    SBE.sub.2 =12.72 millimol/liter (point K).

    SBB.sub.2 =31.50 millimol/liter (point L).

The coordinators are calculated as above:

    pH.sub.K =7.275

    Pco.sub.2 K =27.74 mm Hg

    pH.sub.L =6.994

    Pco.sub.2 L =75.49 mm Hg

From the coordinators for K and L, the in vivo Base Excess line V may becalculated by means of equation 11:

    log Pco.sub.2 =-1.547×pH+12.699.

For the transcutaneously measured Pco₂ of 40 mm Hg, the in vivo pH willbe:

    In vivo pH=7.172 (point D.sub.2).

(c) The in vivo Base Excess line for a patient is calculated from theabove in vivo acid base status

    pH=7.122

    Pco.sub.2 =50 mm Hg

    Po.sub.2 =37.3 mm Hg˜Sat.sub.1 =0.5

    Hb=3.7 millimol/liter, fixed per definition

(which is represented by point C in FIG. 5).

SBE may be calculated from the formulae 6, 7 and 8;

    SBE.sub.1 =-12.2 millimol/liter.

The slope of the Base Excess line may, with approximation, be calculatedfrom the equation:

    α=0.005208×SBE-1.2823-10.sup.(-0.0507×SBE-1.412)

    α.sub.1 =-1.507                                      (16)

The Base Excess line IV is now established

    log Pco.sub.2 =α.sub.1 (pH--7.122)+log 50

pH at 40 mm Pco₂ may now be calculated:

    pH.sub.40 =7.186

If the patient's in vivo Pco₂ (transcutaneously measured Pco₂) changesto 40 mm Hg, in vivo pH changes to

    In vivo pH=7.186 (point D.sub.1).

If the patient's in vivo Po₂ changes to 90 mm Hg, Sat may be calculatedfrom equations 12 and 13, using pH=7.183.

    Sat.sub.2 =0.93.

The change in SBE on change of oxygen saturation from Sat₁ to Sat₂ maybe calculated from equation 14:

    ΔSBE=0.31×Hb(Sat.sub.1 -Sat.sub.2)=-0.5

    SBE.sub.2 =-12.7

The change of pH₄₀ as a function of small changes in SBE may, withapproximation, be calculated from the equation

    ΔpH.sub.40 =10.sup.(-0.01112×SBE.sbsb.1.sup.-1.81487) (17)

ΔSBE

    ΔpH.sub.40 =0.010 (ASBE=0.5)

    ΔpH.sub.40 .sbsb.2 =7.176 (point D.sub.2).

The slope of the Base Excess line for SBE₂ may be calculated fromequation 16:

    α.sub.2 =1.519

The Base Excess line V for Sat=0.93 is now established

    log Pco.sub.2 =α.sub.2 (pH--7.176)+log 40

In vivo pH=7.176(point D₂) for Pco₂ =40 mm Hg and Po₂ =90 mm Hg.

The calculations in this example are more suited for a microcomputerwith limited memory, as these calculations do not require that the BEand the BB curves have been read into the computer.

(d) In vivo Base Excess line is calculated from the same in vivo acidbase status as above, but disregarding saturation.

    pH=7.122

    Pco.sub.2 =50 mm Hg

    Po.sub.2 =37.3 mm Hg˜Sat.sub.1 =0.5

    HB=3.7 millimol/liter, fixed per definition.

The calculation is illustrated by the curve monogram in FIG. 6.

The conditions are here additionally simplified as it has been foundthat the Base Excess lines for a given Hb with approximation intersectin one point.

    Hb=3.7 millimol/liter. (Intersection (pH, log Pco.sub.2)=(5.66, 3.91)).

The Base Excess line IV is hereby established to ##EQU4## If thetranscutaneously measured Pco₂ changes to 40 mm Hg, pH changes to:

    In vivo pH=7.186 (point D).

I claim:
 1. A method for continous or intermittent monitoring of apatient's in vivo plasma pH value, comprising establishing the patient'sacid base status with performance of at least one in vitro determinationon a blood sample withdrawn from the patient, and thereafter determiningthe patient's in vivo plasma pH on the basis of the thus establishedinitial acid base status and on the basis of continuously orintermittently registered results of a non-invasive measurement of thepatient's actual blood Pco₂.
 2. A method according to claim 1,comprising establishing the patient's initial acid base status withperformance of an in vitro determination of pH and Pco₂ on an arterialor capillary blood sample withdrawn from the patient and transferredanaerobically.
 3. A method according to claim 1, comprising establishingthe patient's initial acid base status with performance of in vitrodetermination of pH on an arterial or capillary blood sample withdrawnfrom the patient and transferred anaerobically and on the basis of theresult of a non-invasive measurement of the patient's blood Pco₂performmed simultaneously with the withdrawal of the blood sample.
 4. Amethod according to claim 2, comprising calibrating the in vivo Pco₂measuring equipment on the basis of the result of the in vitro Pco₂measurement and on the basis of the result of a non-invasive measurementof the patient's blood Pco₂ performed simultaneously with the withdrawalof the arterial blood sample.
 5. A method according to claim 2,comprising additionally performing, on the anaerobically transferredarterial or capillary blood sample, a determination of the oxygensaturation, or registering the result of a non-invasive oxygensaturation determination performed simultaneously with the blood samplewithdrawal, and including, in the determinations of the patient's invivo plasma pH for a period thereafter, the result of non-invasiveoxygen saturation determinations performed at the actual times.
 6. Amethod according to claim 1, comprising establishing the patient'sinitial acid base status with performance of in vitro determination ofpH, Pco₂ and an additional blood parameter, said additional bloodparameter being selected from the group consisting of the hemoglobincontent and another blood parameter which is a function of thehemoglobin content, on a non-anaerobically transferred blood samplewithdrawn from the patient, and on the basis of the result ofnon-invasive measurement of the patient's blood Pco₂ performedsimultaneously with the withdrawal of the blood sample.
 7. A methodaccording to claim 6, comprising additionally performing, on the bloodsample, an oxygen saturation determination and registering the result ofa non-invasive oxygen saturation determination performed simultaneouslywith the withdrawal of the blood sample, any differences between theoxygen saturation determination and the result of the non-invasiveoxygen saturation determination being used to correct the initial acidbase status; and in the determinations of the patient's in vivo plasmapH performed for a period thereafter, including the results ofnon-invasive oxygen saturation determinations performed at the actualtimes.
 8. An apparatus for continuous or intermittent monitoring of apatient's in vivo plasma pH, comprising a first input means (13a; 20a)for signals representing results of a non-invasive Pco₂ measurement anda second input means (25a; 27a) for introduction of at least one bloodparameter determined by in vitro measurement, a pH registration unit(12; 12a), a conversion means 21, said pH registration unit beingconnected to the first input means (13a; 20a) through the conversionmeans (21), the conversion means (21) being adapted to perform theconversion of the received Pco₂ signals to pH units as a function of aparameter set read into the conversion means (21), and representing aninitial acid base status, the said parameter set comprising at least oneblood parameter determined by in vitro measurement introduced via thesecond input means (25a; 27a).
 9. An apparatus according to claim 8,comprising a means (24; 26) for introducing at least one blood parameterdetermined in vitro, said means for introducing at least one bloodparameter determined in vitro (24; 26) being connected to the secondinput means (25a; 27a).
 10. An apparatus according to claim 9, in whichthe means (24; 26) for introduction of at least one blood parameterdetermined in vitro is a keyboard.
 11. An apparatus according to claim9, in which the means (24; 26) for the introduction of at least oneblood parameter determined in vitro is pH measuring equipment.
 12. Anapparatus according to claim 9, in which the means (24; 26) forintroduction of at least one blood parameter determined in vitro isblood gas equipment.
 13. An apparatus according to claim 8, which inaddition to the pH registration unit (12; 12a) comprises a Pco₂registration unit (15) connected to the first input means (13a; 20a) forsignals representing the result of a non-invasive Pco₂ measurement. 14.An apparatus according to claim 8, comprising a third input means (14a)for signals representing the result of a non-invasive Po₂ measurement ora non-invasive oxygen saturation measurement, said signals representingthe result of a non-invasive Po₂ measurement or a non-invasive oxygensaturation measurement being at least a part of the parameter set, thesaid third input means communicating with the conversion means (21). 15.An apparatus according to claim 12, and comprising Po₂ registration unit(16) communicating with the said third input means (14a).
 16. Anapparatus according to claim 1, comprising a synchronization means (28;29), at the activation of which the non-invasively measured Pco₂ valueregistered at the activation time and optionally the non-invasivelymeasured Po₂ value registered at the activation time is/are stored inthe conversion means (21).